Gut-Brain axis in Parkinson's disease etiology: The role of lipopolysaccharide

Abstract

Recent studies highlight the initiation of Parkinson's disease (PD) in the gastrointestinal tract, decades before the manifestations in the central nervous system (CNS). This gut-brain axis of neurodegenerative diseases defines the critical role played by the unique microbial composition of the "second brain" formed by the enteric nervous system (ENS). Compromise in the enteric wall can result in the translocation of gut-microbiota along with their metabolites into the system that can affect the homeostatic machinery. The released metabolites can associate with protein substrates affecting several biological pathways. Among these, the bacterial endotoxin from Gram-negative bacteria, i.e., Lipopolysaccharide (LPS), has been implicated to play a definite role in progressive neurodegeneration. The molecular interaction of the lipid metabolites can have a direct neuro-modulatory effect on homeostatic protein components that can be transported to the CNS via the vagus nerve. α-synuclein (α-syn) is one such partner protein, the molecular interactions with which modulate its overall fibrillation propensity in the system. LPS interaction has been shown to affect the protein's aggregation kinetics in an alternative inflammatory pathway of PD pathogenesis. Several other lipid contents from the bacterial membranes could also be responsible for the initiation of α-syn amyloidogenesis. The present review will focus on the intermolecular interactions of α-syn with bacterial lipid components, particularly LPS, with a definite clinical manifestation in PD pathogenesis. However, deconvolution of the sequence of interaction events from the ENS to its propagation in the CNS is not easy or obvious. Nevertheless, the characterization of these lipid-mediated structures is a step towards realizing the novel targets in the pre-emptive diagnoses of PD. This comprehensive description should prompt the correlation of potential risk of amyloidogenesis upon detection of specific paradigm shifts in the microbial composition of the gut.

Keywords: DEST; Gut brain axis; LPS; NMR; Parkinson disease.